The essential feature of this renewal continues to be a collaborative basic neurobiological and clinical research endeavor working toward elucidation of the neurobiological factors in the genesis and treatment of major psychiatric disorders. The proposed research program consists of both preclinical and clinical projects concerned with studying the mechanisms of action of psychotropic drugs and possible biological determinants in schizophrenia and affective illness, through the use of anatomical, histochemical, biochemical, neurophysiological, and behavioral techniques. Preclinical studies relevant to schizophrenia address the effects of both acute and chronic antipsychotic drug treatment on monoaminergic systems and the effect of acute and chronic L-dopa or apomorphine administration on dopaminergic, noradrenergic and serotonergic systems. The clincial section extends to human questions being addressed at a basic level in animals. In clinical studies of schizophrenia the effects of acute, chronic and long-term neuroleptic treatment on serotonergic, noradrenergic and dopaminergic systems will be studied. In studies of the affective disorder particular attention will be paid to systems implicated in the "monoaminergic theory of affective illness" by studying: the effect of chronic administration of tricyclic antidepressant drugs on postsynaptic receptor sensitivity using single-cell techniques; by agonist-induced changes in acoustic startle amplitude as a measure of postsynaptic receptor sensitivity following chronic administration of antidepressant drugs; possible reversal of the effects of chronic locus coeruleus stimulation by chronic antidepressant treatment; the effects of monoaminergic neurotransmission on electrically induced neurophysiological reflexes and the effect of administration of tricyclic antidepressant drugs on such effects; the effects of chronic drugs on clonidine induced changes in hormonal function in animals; and prospective clinical application of the findings which emerge from basic animal studies. Included also will be development of methods relevant to assessment of function of central monoaminergic systems in patients.